Effect of insulin insufficiency on ultrastructure and function in skeletal muscle.

Kopecky, C; Haug, M; Reischl, B; Deshpande, N; Manandhar, B; King, TW; Lee, V; Wilkins, MR; Morris, M; Polly, P; Friedrich, O; Rye, K-A; Cochran, BJ

Effect of insulin insufficiency on ultrastructure and function in skeletal muscle.

Kopecky, C Haug, M Reischl, B Deshpande, N Manandhar, B

King, TW Lee, V Wilkins, MR Morris, M Polly, P Friedrich, O Rye, K-A Cochran, BJ

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Publisher:: Wiley
Publication Type:: Journal Article
Citation:: J Cachexia Sarcopenia Muscle, 2024, 15, (1), pp. 112-123
Issue Date:: 2024-02

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Field	Value	Language
dc.contributor.author	Kopecky, C
dc.contributor.author	Haug, M
dc.contributor.author	Reischl, B
dc.contributor.author	Deshpande, N
dc.contributor.author	Manandhar, B https://orcid.org/0000-0003-1276-6954
dc.contributor.author	King, TW
dc.contributor.author	Lee, V
dc.contributor.author	Wilkins, MR
dc.contributor.author	Morris, M
dc.contributor.author	Polly, P
dc.contributor.author	Friedrich, O
dc.contributor.author	Rye, K-A
dc.contributor.author	Cochran, BJ
dc.date.accessioned	2024-08-21T03:34:17Z
dc.date.available	2023-10-18
dc.date.available	2024-08-21T03:34:17Z
dc.date.issued	2024-02
dc.identifier.citation	J Cachexia Sarcopenia Muscle, 2024, 15, (1), pp. 112-123
dc.identifier.issn	2190-5991
dc.identifier.issn	2190-6009
dc.identifier.uri	http://hdl.handle.net/10453/180432
dc.description.abstract	BACKGROUND: Decreased insulin availability and high blood glucose levels, the hallmark features of poorly controlled diabetes, drive disease progression and are associated with decreased skeletal muscle mass. We have shown that mice with β-cell dysfunction and normal insulin sensitivity have decreased skeletal muscle mass. This project asks how insulin deficiency impacts on the structure and function of the remaining skeletal muscle in these animals. METHODS: Skeletal muscle function was determined by measuring exercise capacity and specific muscle strength prior to and after insulin supplementation for 28 days in 12-week-old mice with conditional β-cell deletion of the ATP binding cassette transporters ABCA1 and ABCG1 (β-DKO mice). Abca1 and Abcg1 floxed (fl/fl) mice were used as controls. RNAseq was used to quantify changes in transcripts in soleus and extensor digitorum longus muscles. Skeletal muscle and mitochondrial morphology were assessed by transmission electron microscopy. Myofibrillar Ca2+ sensitivity and maximum isometric single muscle fibre force were assessed using MyoRobot biomechatronics technology. RESULTS: RNA transcripts were significantly altered in β-DKO mice compared with fl/fl controls (32 in extensor digitorum longus and 412 in soleus). Exercise capacity and muscle strength were significantly decreased in β-DKO mice compared with fl/fl controls (P = 0.012), and a loss of structural integrity was also observed in skeletal muscle from the β-DKO mice. Supplementation of β-DKO mice with insulin restored muscle integrity, strength and expression of 13 and 16 of the dysregulated transcripts in and extensor digitorum longus and soleus muscles, respectively. CONCLUSIONS: Insulin insufficiency due to β-cell dysfunction perturbs the structure and function of skeletal muscle. These adverse effects are rectified by insulin supplementation.
dc.format	Print-Electronic
dc.language	eng
dc.publisher	Wiley
dc.relation.ispartof	J Cachexia Sarcopenia Muscle
dc.relation.isbasedon	10.1002/jcsm.13380
dc.rights	info:eu-repo/semantics/openAccess
dc.subject	0606 Physiology, 1103 Clinical Sciences, 1106 Human Movement and Sports Sciences
dc.subject.classification	3202 Clinical sciences
dc.subject.classification	4201 Allied health and rehabilitation science
dc.subject.classification	4207 Sports science and exercise
dc.subject.mesh	Mice
dc.subject.mesh	Animals
dc.subject.mesh	Insulin
dc.subject.mesh	Muscle, Skeletal
dc.subject.mesh	Muscle Fibers, Skeletal
dc.subject.mesh	Mitochondria
dc.subject.mesh	Muscle, Skeletal
dc.subject.mesh	Mitochondria
dc.subject.mesh	Animals
dc.subject.mesh	Mice
dc.subject.mesh	Insulin
dc.subject.mesh	Muscle Fibers, Skeletal
dc.subject.mesh	Mice
dc.subject.mesh	Animals
dc.subject.mesh	Insulin
dc.subject.mesh	Muscle, Skeletal
dc.subject.mesh	Muscle Fibers, Skeletal
dc.subject.mesh	Mitochondria
dc.title	Effect of insulin insufficiency on ultrastructure and function in skeletal muscle.
dc.type	Journal Article
utslib.citation.volume	15
utslib.location.activity	Germany
utslib.for	0606 Physiology
utslib.for	1103 Clinical Sciences
utslib.for	1106 Human Movement and Sports Sciences
pubs.organisational-group	University of Technology Sydney
pubs.organisational-group	University of Technology Sydney/Faculty of Health
pubs.organisational-group	University of Technology Sydney/Faculty of Health/Graduate School of Health
pubs.organisational-group	University of Technology Sydney/Faculty of Health/Graduate School of Health/GSH.Pharmacy
utslib.copyright.status	open_access	*
dc.rights.license	This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License (CC BY-NC 4.0). To view a copy of this license, visit https://creativecommons.org/licenses/by-nc/4.0/
dc.date.updated	2024-08-21T03:34:11Z
pubs.issue	1
pubs.publication-status	Published
pubs.volume	15
utslib.citation.issue	1

Abstract:

BACKGROUND: Decreased insulin availability and high blood glucose levels, the hallmark features of poorly controlled diabetes, drive disease progression and are associated with decreased skeletal muscle mass. We have shown that mice with β-cell dysfunction and normal insulin sensitivity have decreased skeletal muscle mass. This project asks how insulin deficiency impacts on the structure and function of the remaining skeletal muscle in these animals. METHODS: Skeletal muscle function was determined by measuring exercise capacity and specific muscle strength prior to and after insulin supplementation for 28 days in 12-week-old mice with conditional β-cell deletion of the ATP binding cassette transporters ABCA1 and ABCG1 (β-DKO mice). Abca1 and Abcg1 floxed (fl/fl) mice were used as controls. RNAseq was used to quantify changes in transcripts in soleus and extensor digitorum longus muscles. Skeletal muscle and mitochondrial morphology were assessed by transmission electron microscopy. Myofibrillar Ca2+ sensitivity and maximum isometric single muscle fibre force were assessed using MyoRobot biomechatronics technology. RESULTS: RNA transcripts were significantly altered in β-DKO mice compared with fl/fl controls (32 in extensor digitorum longus and 412 in soleus). Exercise capacity and muscle strength were significantly decreased in β-DKO mice compared with fl/fl controls (P = 0.012), and a loss of structural integrity was also observed in skeletal muscle from the β-DKO mice. Supplementation of β-DKO mice with insulin restored muscle integrity, strength and expression of 13 and 16 of the dysregulated transcripts in and extensor digitorum longus and soleus muscles, respectively. CONCLUSIONS: Insulin insufficiency due to β-cell dysfunction perturbs the structure and function of skeletal muscle. These adverse effects are rectified by insulin supplementation.

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http://hdl.handle.net/10453/180432